PROJECT SUMMARY Age-associated cognitive decline is an important human condition that varies in extent among individuals. This variation likely arises from a complex interplay of genetic and environmental factors. Caffeine is the most commonly ingested behaviorally active substance in the world, and a growing body of literature points to the premise that caffeine may provide a safe, effective, readily available, and inexpensive therapeutic agent against cognitive decline. However, factors that contribute to variation in caffeine metabolism may interact with caffeine intake and modify its association with cognitive decline. Furthermore, caffeine targets genes and pathways potentially impacting cognitive decline and thus an opportunity to advancing our understanding of this condition may be missed if variation in caffeine metabolism is left unaccounted for. Dr. Cornelis proposes a training and research plan that will contribute to her goal to become an independent investigator of systems epidemiology of nutrition and cognitive decline. To acquire training in i) cognitive function assessment ii) epidemiology of cognitive decline and iii) neuropathological aspects of cognitive decline and Alzheimer's disease, she will work closely with a team of internationally recognized mentors from two highly reputable institutes committed to aging research and engage in training activities including coursework, one-on-one and small group sessions, seminars and conferences, observation and hands-on practicum including a pilot study of caffeine and brain DNA methylation. She will apply her training to the first comprehensive and highly efficient analysis of the joint effects of genetics and caffeine on cognitive decline. Composite indices of caffeine metabolic rate and caffeine exposure will be used in an epidemiological meta-analytical framework to examine gene?caffeine intake interactions and cognitive decline and to discover novel loci for this condition by modeling SNP?caffeine exposure interactions on a genome-wide scale. Dr. Cornelis's research will provide critical insights into the role that caffeine potentially plays in slowing cognitive decline and has potential to uncover novel biological pathways underlying this condition. Results of this work should foster new lines of investigation for cognitive impairment and for developing novel behavioral and pharmacological avenues for safe and effective treatment and prevention. Moreover, the experience and knowledge obtained from the completion of Dr. Cornelis's training and research plan will allow her to obtain R01 funding to acquire additional systems-level data for a more detailed mechanistic view of how caffeine or other dietary factors impact cognitive decline.